The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to describe or constitute prior art to the invention.
Cellular signal transduction is a fundamental mechanism whereby external stimuli that regulate diverse cellular processes are relayed to the interior of cells. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins, which enables regulation of the activity of mature proteins by altering their structure and function. Enzymes that mediate phosphorylation of cellular effectors fall into two classes. While protein phosphatases hydrolyze phosphate moieties from phosphoryl protein substrates, protein kinases transfer a phosphate moiety from adenosine triphosphate to protein substrates. The converse functions of protein kinases and protein phosphatases balance and regulate the flow of signals in signal transduction processes.
Kinases largely fall into two groups, those specific for phosphorylating serines and threonines (STKs), and those specific for phosphorylating tyrosines (TKs). The protein phosphatases can also be classified as being specific for either serine/threonine (STPs) or tyrosine (PTPs). The known enzymes, both kinase and phosphatases, can be divided into two groups—receptor and non-receptor type proteins. Most receptor-type protein tyrosine phosphatases (RTPs) contain two conserved catalytic tyrosine phosphatase domains each of which encompasses a segment of 240 amino acid residues (Saito et al, Cell Growth and Diff., 2:59, 1991). The RPTPs can be subclassified further based upon the amino acid sequence diversity of their extracellular domains (Saito, et al., supra, Krueger, et al., PNAS 89:7417, 1992).
Alignment of primary amino acid sequences of known phosphatases and kinases shows that their catalytic domains share common amino acid sequences with other enzymes in their respective classes. This observation has facilitated efforts of cloning protein phosphatases from multiple organisms and tissues. Probing cDNA libraries with polynucleotides complementary to cDNA encoding protein phosphatase consensus sequences has identified cDNAs resembling protein phosphatase or kinase sequences via the polymerase chain reaction (PCR). Some polypeptide molecules encoded by these cDNAs have enzymatic activity.
Tyrosine phosphatases can down-regulate the catalytic activity of protein kinases involved in cell proliferation and are therefore thought to be possible candidate anti-cancer proteins. In addition to their role in cellular proliferation, protein phosphatases are thought to be involved in cellular differentiation processes. Cell differentiation occurs in some cells upon nerve growth factor (NGF) or epidermal growth factor (EGF) stimulation. Cellular differentiation is characterized by rapid membrane ruffling, cell flattening, and increases in cell adhesion. Chao, Cell 68:995-997, 1992.
In view of the above, it can be seen that a need exists to identify additional proteins whose inappropriate activity may lead to cancer or other disorders so that pharmaceutical compounds for the treatment of those disorders might also be identified.